Bestatin and amastatin are two low-molecular weight inhibitors of aminopeptidases. In vivo these inhibitors have been shown to have immune stimulating properties and may provide a basis for the treatment of cancer by stimulating the body's own resistance mechanisms. This proposal will characterize the interaction of bestatin and amastatin and several structurally derived inhibitors, with leucine aminopeptidase (LSP), aminopeptidase A (AP-A) and aminopeptidase B. Specifically we will determine which groups are needed for maximal inhibition of aminopeptidases and how these bind to the enzyme. The slow binding of these inhibitors to LAP will be characterized. The structure-kinetic data will be applied to the development of more potent inhibitors of these enzymes, and to the development of inhibitors specific for angiotensinase A and enkephalin aminopeptidase.